The primary goal of this project is to determine the anatomical organization, molecular phenotype, and electrophysiological properties of locus coeruleus (LC) neurons that innervate sub-regions of the rat prefrontal and motor cortex. The prefrontal cortex (PFC) including its sub-regions the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC), and the primary motor cortex (M1) are innervated by the LC and subject to the modulatory actions of its primary transmitter, norepinephrine (NE). Each of the PFC sub-regions mediates distinct aspects of executive function that are compromised in many neuropsychiatric disorders including ADHD, PTSD, and schizophrenia. Likewise, the NE system has been implicated in the control of many PFC-dependent behavioral functions including flexible and sustained attention. The first aim of the proposed research will include retrograde tracing studies and immunohistochemical procedures to identify and characterize the subsets of NE-containing neurons within the LC that project to each PFC sub-region. In this and all subsequent aims M1 will serve as a non-cognitive brain region for comparison. The second aim of the project will determine the molecular complement of each class of projection cells by examining their transcriptomes and their expression levels of selected genes that are critical for noradrenergic function using combinations of laser micro-dissection, RNA microarray analysis and qRT-PCR. The third aim will profile individual LC-PFC and M1 projection cells on the basis of membrane properties, synaptic responsiveness, and sensitivity to drug activation using whole cell patch clamp techniques. These studies will provide a more complete understanding of the anatomical, molecular, and physiological attributes of the LC-cortical projection and challenge the longstanding notion that the LC is a functionally homogeneous cluster of NE-containing neurons that exert uniform modulatory effects across all LC- noradrenergic terminal fields, simultaneously. Instead, the general working hypothesis is that the LC-NE system operates by heterogeneous and asynchronous modulation of modality-specific terminal fields. This new theoretical construct has far reaching implications for our understanding of normal brain function and treatment of many neuropsychiatric disorders that involve noradrenergic and prefrontal cortical dysfunction.